1. Field of the Invention
The present invention is directed to methods of reducing symptoms associated with an abrupt reduction in an endogenous or exogenous chemical in subjects, the methods comprising: (a) administering to the subjects a single dosage form comprising an active agent, wherein the release rate of the active agent from the single dosage form tapers throughout the administration; and (b) removing the single dosage form from the subjects after the release rate of the active agent is at or below a terminal symptom threshold level.
2. Background Art
Continual administration of an active agent often involves either a “constant dosage” regimen or a “step-down dosage” regimen. A “constant dosage” regimen requires administering an unvarying amount of an active agent at regular time intervals, e.g., in a daily dosage. For example, hormone replacement therapy often requires administering a constant daily dosage of an estrogen, thereby restoring the estrogenic hormones to their normal endogenous levels (see U.S. Pat. Nos. 5,210,081; 5,547,948; RE36,247; and see also physician's leaflet for ESTRING® (estradiol vaginal ring, Pfizer, Inc., New York, N.Y., August 2008). Hormone replacement therapy to treat menopause can be administered for a period of several months to several years.
Alternatively, for some conditions, a step-down regimen is used. A “step-down dosage” regimen requires administering an active agent in an amount that decreases over time in a step-wise or tiered manner. For example, nicotine replacement therapy is a stepdown dosage regimen indicated to reduce withdrawal symptoms, including nicotine cravings, associated with quitting smoking. For example, NICODERM CQ® (see U.S. Pat. Nos. 5,004,610; 5,342,623; 5,344,656; 5,364,630; 5,462,745; 5,508,038; 5,633,008; and 6,165,497, Glaxo SmithKline, United Kingdom) administers a once-daily dosage of nicotine for a period of 10 weeks in a decreasing series of dosage levels. During the first six weeks of the regimen, 21 mg of nicotine is administered per day, followed by two weeks of administering 14 mg of nicotine per day, and ending with administering 7 mg of nicotine per day for the final two weeks of the regimen. These doses of nicotine are not sufficient to raise the systemic circulating level of nicotine to that attained while smoking tobacco products, but are sufficient to alleviate the symptoms associated with nicotine withdrawal, and thus helps subjects in the cessation of tobacco use.
Step-down dosage regimens can also be administered to subjects in need of hormone replacement therapy. For example, see U.S. Appl. Pub. No. 2003/0216366 AI. Step-down dosage regimens are also frequently administered to subjects discontinuing the use of a barbiturate, a beta-adrenergic receptor antagonist, or an opiate. For example, withdrawal symptoms associated with addiction to heroin can be greatly reduced by administering multiple dosage forms of a long-acting opioid such as methadone (see labeling for METHADOSE®, Mallinckrodt, Hazelwood, Mo., February 2008). These regimens typically last about three to seven days, or longer, during which time the amount of methadone in each dosage is decreased in a step-down manner to alleviate the symptoms associated with heroin withdrawal. However, with both the constant dosage regimens and the step-down regimens, there are one or more periods in which there is an abrupt reduction in the amount of active agent administered. In the case of a constant regimen, the abrupt reduction in active agent occurs when the treatment period ends. In the case of the step-down regimen, the abrupt reduction in active agent occurs whenever there is a “step-down” to the next lower dosage, as well as when the treatment ends. The abrupt reduction of a regular dosage regimen of a substance can result in the development of withdrawal symptoms in a subject, and potentially, in an adverse health condition. Thus, there is a need for a single dosage form containing an active agent, and methods of administering an active agent wherein the release rate of the active agent tapers during administration that avoid such problems.